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1.
Anticancer Res ; 40(1): 35-52, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892551

RESUMO

BACKGROUND/AIM: Co-expression of c-Met and ALDH1A3 indicates a poor prognosis in stage III-IV breast cancers and contributes to cell proliferation and tumor formation by ALDH1-positive breast CSCs. PKCλ is overexpressed and contributes to a poor prognosis in several cancers. MATERIALS AND METHODS: A breast cancer genomics data set (METABRIC, n=2509) was downloaded and analyzed, as was the effect c-Met and PKCλ inhibitors on ALDH1high cell viability and tumor-sphere formation. RESULTS: c-Met expression correlates with expression of PKCλ in breast cancer. Stage III-IV breast cancer patients with c-Methigh PKCλhigh ALDH1A3high have a poorer prognosis than patients with c-Metlow PKCλlow ALDH1A3low Foretinib and auranofin suppressed cell viability and tumor-sphere formation by ALDH1high cells. These results suggest that c-Met and PKCλ are cooperatively involved in cancer progression and contribute to poor prognoses in breast cancer. CONCLUSION: c-Met and PKCλ are potentially useful prognostic markers and therapeutic targets in late-stage breast cancer.


Assuntos
Aldeído Oxirredutases/genética , Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Proteína Quinase C/genética , Proteínas Proto-Oncogênicas c-met/genética , Aldeído Oxirredutases/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo
2.
Biochem Biophys Rep ; 20: 100684, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31517069

RESUMO

Passion fruit seed extract (PFSE), a product rich in stilbenes such as piceatannol and scirpusin B, has various physiological effects. It is unclear whether PFSE and its stilbene derivatives inhibit cancer cell proliferation via human glyoxalase I (GLO I), the rate-limiting enzyme for detoxification of methylglyoxal. We examined the anticancer effects of PFSE in two types of human cancer cell lines with different GLO I expression levels, NCI-H522 cells (highly-expressed GLO I) and HCT116 cells (lowly-expressed GLO I). PFSE and its stilbenes inhibited GLO I activity. In addition, PFSE and its stilbenes supressed the cancer cell proliferation of NCI-H522 cells more than HCT116 cells. These observations suggest that PFSE can provide a novel anticancer strategy for prevention and treatment.

3.
Bioorg Med Chem Lett ; 29(11): 1390-1394, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935798

RESUMO

The antibacterial and cytotoxic activity of seven racemic lactams and both enantiomers of flavipucine were evaluated. Of the compounds tested in this study, flavipucine and phenylflavipucine displayed bactericidal activity against Bacillus subtilis. These results indicate that the pyridione epoxide moiety is a pharmacophore for antibacterial activity against B. subtilis. Flavipucine showed cytotoxic activity against several cancer cells. The cytotoxic activity of flavipucine against human leukemia HL-60 cells is as strong as that of SN-38, the active metabolite of irinotecan. In contrast, the cytotoxic activity of flavipucine against nonneoplastic HEK293 cells and human normal MRC-5 cells is weaker than that of SN-38. No significant differences in the biological activity of the racemates or enantiomers of flavipucine were observed.

4.
Biochem Biophys Res Commun ; 511(3): 665-670, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30826057

RESUMO

The interaction of high mobility group box 1 (HMGB1), which is secreted from immune and dying cells during cellular infection and injury, and receptor for advanced glycation end-products (RAGE) appears to be critical for acute and chronic inflammatory disorders. Here we designed a unique cyclic ß-hairpin peptide (Pepb2), which mimics the predicted RAGE-binding domain of HMGB1. Pepb2 competitively inhibited HMGB1/RAGE interaction. We then identified papaverine as a Pepb2 mimetic by in silico 3D-structural similarity screening from the DrugBank library. Papaverine was found to directly inhibit HMGB1/RAGE interaction. It also suppressed the HMGB1-mediated production of pro-inflammatory cytokines, IL-6 and TNF-α, in mouse macrophage-like RAW264.7 cells and bone marrow-derived macrophages. In addition, papaverine attenuated mortality in cecal ligation puncture-induced sepsis model mice. Taken together, these findings indicate that papaverine could become a useful therapeutic against HMGB1/RAGE-mediated sepsis and other inflammatory diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Proteína HMGB1/antagonistas & inibidores , Inflamação/tratamento farmacológico , Papaverina/uso terapêutico , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Sepse/tratamento farmacológico , Animais , Feminino , Proteína HMGB1/imunologia , Inflamação/complicações , Inflamação/imunologia , Interleucina-6/imunologia , Camundongos , Camundongos Endogâmicos ICR , Células RAW 264.7 , Receptor para Produtos Finais de Glicação Avançada/imunologia , Sepse/complicações , Sepse/imunologia , Fator de Necrose Tumoral alfa/imunologia
5.
Oncotarget ; 9(92): 36515-36529, 2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30559934

RESUMO

Glyoxalase 1 (GLO1) is a ubiquitous enzyme involved in the detoxification of methylglyoxal, a cytotoxic byproduct of glycolysis that induces apoptosis. In this study, we found that GLO1 gene expression correlates with neoplasm histologic grade (χ 2 test, p = 0.002) and is elevated in human basal-like breast cancer tissues. Approximately 90% of basal-like cancers were grade 3 tumors highly expressing both GLO1 and the cancer stem cell marker ALDH1A3. ALDH1high cells derived from the MDA-MB 157 and MDA-MB 468 human basal-like breast cancer cell lines showed elevated GLO1 activity. GLO1 inhibition using TLSC702 suppressed ALDH1high cell viability as well as the formation of tumor-spheres by ALDH1high cells. GLO1 knockdown using specific siRNAs also suppressed ALDH1high cell viability, and both TLSC702 and GLO1 siRNA induced apoptosis in ALDH1high cells. These results suggest GLO1 is essential for the survival of ALDH1-positive breast cancer stem cells. We therefore conclude that GLO1 is a potential therapeutic target for treatment of basal-like breast cancers.

6.
Arch Biochem Biophys ; 638: 1-7, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29225125

RESUMO

Many cancer cells undergo metabolic reprogramming known as the Warburg effect, which is characterized by a greater dependence on glycolysis for ATP generation, even under normoxic conditions. Glyoxalase I (GLO I) is a rate-limiting enzyme involved in the detoxification of cytotoxic methylglyoxal formed in glycolysis and which is known to be highly expressed in many cancer cells. Thus, specific inhibitors of GLO I are expected to be effective anticancer drugs. We previously discovered a novel GLO I inhibitor named TLSC702. Although the strong inhibitory activity of TLSC702 was observed in the in vitro enzyme assay, higher concentrations were required to induce apoptosis at the cellular level. One of the proposed reasons for this difference is that cancer cells alter the energy metabolism leading them to become more dependent on mitochondrial respiration than glycolysis (Metabolic shift) to avoid apoptosis induction. Thus, we assumed that combination of TLSC702 with shikonin-a specific inhibitor of pyruvate kinase M2 (PKM2) that acts as a driver of TCA cycle by supplying pyruvate and which is known to be specifically expressed in cancer cells-would have anticancer effects. We herein show the anticancer effects of combination treatment with TLSC702 and shikonin, and a possible anticancer mechanism.


Assuntos
Apoptose , Proteínas de Transporte/metabolismo , Lactoilglutationa Liase/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/enzimologia , Piruvato Quinase/metabolismo , Hormônios Tireóideos/metabolismo , Butiratos/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Ciclo do Ácido Cítrico/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactoilglutationa Liase/antagonistas & inibidores , Lactoilglutationa Liase/genética , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Naftoquinonas/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Piruvato Quinase/antagonistas & inibidores , Piruvato Quinase/genética , Ácido Pirúvico/metabolismo , Tiazóis/farmacologia , Hormônios Tireóideos/genética
7.
Genes Cancer ; 8(7-8): 628-639, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28966724

RESUMO

c-Met is a receptor-type tyrosine kinase, which is involved in a wide range of cellular responses such as proliferation, motility, migration and invasion. It has been reported to be overexpressed in various cancers. However, the role of c-Met in breast cancer stem cells (CSCs) still remains unclear. We herein, show that c-Met expression is significantly elevated in Basal-like type of breast cancer in comparison with other subtypes. High expression of c-Met strongly correlated with the expression of two CSC markers, ALDH1A3 and CD133 in breast cancers. In addition, breast cancers at tumor stage III-IV expressing both c-Methigh and ALDH1A3high had poor prognosis. Furthermore, treatment with c-Met inhibitors (Crizotinib, Foretinib, PHA-665752 and Tivantinib) in MDA-MB157 cells with high c-Met protein expression resulted in significant suppression in cell viability, contrary to MDA-MB468 cells with low c-Met protein expression. These c-Met inhibitors also suppressed cell viability and tumor-sphere formation of ALDH1high breast cancer cells with high c-Met expression. These results suggest that c-Met in ALDH1 positive CSCs seems to play an important role in breast cancer repopulation. Therefore, we conclude that c-Met is a potential therapeutic target in ALDH1 positive breast CSCs.

8.
Bioorg Med Chem Lett ; 27(5): 1169-1174, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28169168

RESUMO

Human glyoxalase I (GLO I), a rate-limiting enzyme for detoxification of methylglyoxal (MG), a by-product of glycolysis, is known to be a potential therapeutic target for cancer. Here, we searched new scaffolds from natural compounds for designing novel GLO I inhibitors and found trans-stilbene scaffold. We examined the inhibitory abilities to human GLO I of commercially available trans-stilbene compounds. Among them, piceatannol was found to have the most potent inhibitory activity against human GLO I. Piceatannol could inhibit the proliferation of human lung cancer NCI-H522 cells, which are dependent on GLO I for survival, in a dose- and time-dependent manner. In addition, piceatannol more significantly inhibited the proliferation of NCI-H522 cells than that of NCI-H460 cells, which are less dependent on GLO I. Importantly, overexpression of GLO I in NCI-H522 cells resulted in less sensitive to the antiproliferative activity of piceatannol. Taken together, this is the first report demonstrating that piceatannol inhibits GLO I activity and the GLO I-dependent proliferation of cancer cells. Furthermore, we determined a pharmacophore for novel inhibitors of human GLO I by computational simulation analyses of the binding mode of piceatannol to the enzyme hot spot in the active site. We suggest that piceatannol is a possible lead compound for the development of novel GLO I inhibitory anticancer drugs.


Assuntos
Inibidores Enzimáticos/farmacologia , Lactoilglutationa Liase/antagonistas & inibidores , Estilbenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia
9.
Biol Pharm Bull ; 39(5): 869-73, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27150153

RESUMO

Human glyoxalase I (hGLO I) is a rate-limiting enzyme in the pathway for detoxification of apoptosis-inducible methylglyoxal (MG), which is the side product of tumor-specific aerobic glycolysis. GLO I has been reported to be overexpressed in various types of cancer cells, and has been expected as an attractive target for the development of new anticancer drugs. We previously discovered a novel inhibitor of hGLO I, named TLSC702, by our in silico screening method. Here, we show that TLSC702 inhibits the proliferation of human leukemia HL-60 cells and induces apoptosis in a dose-dependent manner. In addition, TLSC702 more significantly inhibits the proliferation of human lung cancer NCI-H522 cells, which highly express GLO I, than that of GLO I lower-expressing human lung cancer NCI-H460 cells. Furthermore, this antiproliferative effect of TLSC702 on NCI-H522 cells is in a dose- and time-dependent manner. These results suggest that TLSC702 can induce apoptosis in tumor cells by GLO I inhibition, which lead to accumulation of MG. Taken together, TLSC702 could become a unique seed compound for the generation of novel chemotherapeutic drugs targeting GLO I-dependent human tumors.


Assuntos
Antineoplásicos/farmacologia , Butiratos/farmacologia , Lactoilglutationa Liase/antagonistas & inibidores , Tiazóis/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fragmentação do DNA , Humanos
10.
Bioorg Med Chem ; 19(20): 5935-47, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21937235

RESUMO

Neutral endopeptidase (NEP) plays a key role in the metabolic inactivation of various bioactive peptides such as atrial natriuretic peptide (ANP), endothelins, and enkephalins. Furthermore, NEP is known to work as elastase in skin fibroblast. Therefore, effective inhibitors of NEP offer significant therapeutic interest as antihypertensives, analgesics, and skin anti-aging agents. Recently, the X-ray crystal structure of human NEP complexed with phosphoramidon has been reported and provided insights into the active site specificity of NEP. Here, we designed new inhibitors by using in silico molecular modeling and synthesized them by short steps. Expectedly, we found highly effective inhibitors with sub-nanomolar levels of IC(50) values. These results indicate that our structure-based molecular designing program is useful for obtaining novel NEP inhibitors. Furthermore, these inhibitors may be attractive leads for the generation of new pharmaceuticals for NEP-related diseases.


Assuntos
Dipeptídeos/química , Dipeptídeos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Neprilisina/antagonistas & inibidores , Neprilisina/química , Sequência de Aminoácidos , Cristalografia por Raios X , Desenho de Drogas , Humanos , Modelos Químicos , Dados de Sequência Molecular , Estrutura Molecular , Neprilisina/metabolismo , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 21(14): 4337-42, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21669529

RESUMO

The human glyoxalase I (hGLO I), which is a rate-limiting enzyme in the pathway for detoxification of apoptosis-inducible methylglyoxal (MG), has been expected as an attractive target for the development of new anti-cancer drugs. We have previously identified a natural compound myricetin as a substrate transition-state (Zn(2+)-bound MG-glutathione (GSH) hemithioacetal) mimetic inhibitor of hGLO I. Here, we constructed a hGLO I/inhibitor 4-point pharmacophore based on the binding mode of myricetin to hGLO I. Using this pharmacophore, in silico screening of chemical library was performed by docking study. Consequently, a new type of compound, which has a unique benzothiazole ring with a carboxyl group, named TLSC702, was found to inhibit hGLO I more effectively than S-p-bromobenzylglutathione (BBG), a well-known GSH analog inhibitor. The computational simulation of the binding mode indicates the contribution of Zn(2+)-chelating carboxyl group of TLSC702 to the hGLO I inhibitory activity. This implies an important scaffold-hopping of myricetin to TLSC702. Thus, TLSC702 may be a valuable seed compound for the generation of a new lead of anti-cancer pharmaceuticals targeting hGLO I.


Assuntos
Inibidores Enzimáticos/química , Flavonoides/química , Lactoilglutationa Liase/antagonistas & inibidores , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Humanos , Lactoilglutationa Liase/genética , Lactoilglutationa Liase/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
12.
Biol Pharm Bull ; 34(2): 290-4, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21415543

RESUMO

Caspases cleave several cellular proteins to execute cell death by apoptosis. The identification of novel substrates of caspases could provide an important clue for elucidation of new apoptosis signaling pathways. In this study, we tested whether an amyloid precursor protein (APP) binding protein Fe65 is proteolytically degraded in neuronal cell death by apoptosis, using a neuron-like cell line, human neuroblastoma SH-SY5Y cells. When treated with DNA damaging agents, etoposide (ETP) and camptothecin (CPT), SH-SY5Y cells underwent apoptosis in a dose-dependent manner. Interestingly, Fe65 (97 kDa) was cleaved to a 65 kDa product during DNA damage-induced apoptosis. Furthermore, the cleavage of Fe65 was accompanied by activation of caspases-9 and -3. The restriction cleavage of Fe65 was completely suppressed by the treatment with a pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(OMe) fluoromethylketone (z-VAD-fmk). These results reveal the restriction cleavage of Fe65 by caspases during DNA damage-induced apoptosis. Since Fe65 has been shown to suppress APP processing to amyloid ß (Aß) production, our findings may provide a new insight into the molecular mechanism by which DNA damage induces Aß production and subsequent neuronal cell death in Alzheimer's disease (AD).


Assuntos
Peptídeos beta-Amiloides/biossíntese , Precursor de Proteína beta-Amiloide/metabolismo , Apoptose/fisiologia , Caspases/metabolismo , Dano ao DNA/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Doença de Alzheimer/metabolismo , Camptotecina/farmacologia , Linhagem Celular Tumoral , Citotoxinas/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Etoposídeo/farmacologia , Humanos , Neuroblastoma , Neurônios/metabolismo , Neurônios/patologia , Transdução de Sinais
13.
Biol Pharm Bull ; 34(1): 146-9, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21212533

RESUMO

Glycogen synthase kinase-3ß (GSK-3ß) is a serine/threonine kinase that phosphorylate protein substrates involved in Alzheimer's disease (AD), such as microtubule-associated protein tau and amyloid precursor protein (APP). GSK-3ß consists of two splice variants; the major short form (GSK-3ß1) distributes in many organs and the minor long form (GSK-3ß2), whose structural difference is the insert of only 13 amino acid residues to the C-terminal side of the catalytic site of GSK-3ß1, is present in central nervous system. However, the physiological significances of the two variants are unclear. Here we examined whether the phosphorylation activities of two variants to tau and APP are different in cells. We found that GSK-3ß2 has lower phosphorylation activity to tau at AD-relevant epitope (Ser396) than GSK-3ß1 in cells, whereas the two variants exhibit equivalent levels of phosphorylation activities to APP. Recombinant GSK-3ß2 has also lower phosphorylation activity to tau than GSK-3ß1 in vitro, although the phosphorylation activities of the two variants to a synthetic peptide substrate pGS-2 are comparable. Furthermore, the deletion of the C-terminal tail (CT) of GSK-3ß2 resulted in considerable reduction of tau phosphorylation activity as compared with GSK-3ß1, suggesting that the lower phosphorylation activity of GSK-3ß2 to tau is attributed to weak interaction with tau through its unique higher-order structure of CT constructed by the 13 amino acids insertion. Such information may provide a clue for understanding of the physiological significance of the two splice variants of GSK-3ß and a new insight into the regulation of tau phosphorylation in central nervous system.


Assuntos
Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas tau/metabolismo , Células HEK293 , Humanos , Fosforilação , Isoformas de Proteínas , Estrutura Terciária de Proteína
14.
Arch Biochem Biophys ; 506(2): 188-93, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21093407

RESUMO

High mobility group box 1 (HMGB1) initially identified as a non-histone chromosomal protein, which mainly functions as chromatin structure and transcriptional regulation, has been recently reported to be secreted into extracellular milieu in necrosis and apoptosis, and act as a proinflammatory mediator. However, the mechanism by which apoptotic cells release HMGB1 is not clear. In this study, we found that staurosporine (apoptosis-inducer)-induced HMGB1 release was associated with nucleosomal DNA fragmentation catalyzed by caspase-activated DNase (CAD) in WEHI-231 cells. Importantly, this event was effectively attenuated by the treatment of a pan-caspase inhibitor, Z-VAD-fmk, and by the inhibition of CAD-mediated DNA fragmentation by the expression of caspase-resistant inhibitor of CAD (ICAD-CR). In WEHI-231/ICAD-CR and WEHI-231/Puro cells, DNase γ-catalyzed nucleosomal DNA fragmentation occurred by anti-IgM antibody treatment was critical for HMGB1 release. Furthermore, in DNase γ stably-expressing HeLa S3 cells (HeLa S3/γ), the release of HMGB1 accompanied with nucleosomal DNA fragmentation was more apparent than that in parental HeLa S3 cells in which DNA fragmentation was scarcely observed. Taken together, these date suggest that nucleosomal DNA fragmentation catalyzed by CAD or DNase γ plays a pivotal role in HMGB1 release.


Assuntos
Apoptose/fisiologia , Fragmentação do DNA , Proteína HMGB1/metabolismo , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Linhagem Celular , Inibidores de Cisteína Proteinase/farmacologia , Fragmentação do DNA/efeitos dos fármacos , Desoxirribonucleases/metabolismo , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Células HeLa , Humanos , Camundongos , Nucleossomos/efeitos dos fármacos , Nucleossomos/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Estaurosporina/farmacologia
15.
Bioorg Med Chem ; 19(1): 168-71, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21167721

RESUMO

High mobility group box1 (HMGB1) is a non-histone chromatin chromosomal protein playing an important role in chromatin architecture and transcriptional regulation. Recently, HMGB1 has been shown to be secreted into extracellular milieu in necrosis and apoptosis, and involved in inflammatory responses. However, the mechanism by which apoptotic cells release HMGB1 is unclear. In this study, to investigate the mechanism of HMGB1 release, we searched inhibitors of HMGB1 release from apoptotic cells. As a result, three compounds, 4-(4,6-dichloro-[1,3,5]-triazin-2-ylamino)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-benzoic acid (DR396), Pontacyl Violet 6R (PV6R), and Fmoc-D-Cha-OH (FDCO) in our in-house chemical library were found to inhibit HMGB1 release from staurosporine (STS)-induced apoptotic HeLa S3 cells. Interestingly, these three compounds have been previously categorized into apoptotic DNase γ inhibitors. Therefore, we examined whether apoptotic nucleosomal DNA fragmentation is involved in the release of HMGB1 during apoptosis. Expectedly, DR396, which is the most potent and specific inhibitor of DNase γ, was found to almost completely inhibit both HMGB1 release and internucleosomal DNA cleavage in HeLa S3 cells transfected with DNase γ expression vector and stably expressing DNase γ (HeLa S3/γ cells). These results clearly suggest that nucleosomal DNA fragmentation catalyzed by DNase γ is critical in the release of HMGB1 from apoptotic cells.


Assuntos
Apoptose/efeitos dos fármacos , Endodesoxirribonucleases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Fluoresceínas/farmacologia , Triazinas/farmacologia , Proteína HMGB1/metabolismo , Células HeLa , Humanos
16.
Bioorg Med Chem ; 18(22): 8112-8, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20947360

RESUMO

Tyrosinase inhibitors are important agents for cosmetic products. We examined here the inhibitory effects of three isomers of thujaplicins (α, ß and γ) on mushroom tyrosinase and analyzed their binding modes using a homology model from the crystal structure of Streptomyces castaneoglobisporus tyrosinase (PDB ID: 1wx2). All the thujaplicins were found to be competitive inhibitors and γ-thujaplicin has the most potent inhibitory activity (IC(50)=0.07µM). It is noted that there are good correlations between their observed IC(50) values and their binding free energies calculated by MM-GB/SA. The binding modes of thujaplicins were predicted to be similar to that of Tyr98 of caddie protein (ORF378), which was co-crystallized with S. castaneoglobisporus tyrosinase. Furthermore, free energy decomposition analysis indicated that the potent inhibitory activity of γ-thujaplicin is due to the interactions with His242, Val243 and Pro257 (hot spot amino acid residues) at the active site of tyrosinase. These results provide a novel structural insight into the hot spot of mushroom tyrosinase for the specific binding of γ-thujaplicin.


Assuntos
Agaricales/enzimologia , Aminoácidos/química , Monofenol Mono-Oxigenase/química , Monoterpenos/química , Tropolona/análogos & derivados , Sequência de Aminoácidos , Proteínas de Bactérias/química , Sítios de Ligação , Ligação Competitiva , Domínio Catalítico , Cristalografia por Raios X , Isomerismo , Cinética , Dados de Sequência Molecular , Monofenol Mono-Oxigenase/metabolismo , Monoterpenos/farmacologia , Ligação Proteica , Alinhamento de Sequência , Streptomyces/enzimologia , Tropolona/química , Tropolona/farmacologia
17.
Bioorg Med Chem ; 18(19): 7029-33, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20801663

RESUMO

Glyoxalase I (GLO I) is the rate-limiting enzyme for detoxification of methylglyoxal (MG), a side-product of glycolysis, which is able to induce apoptosis. Since GLO I is known to be highly expressed in the most tumor cells and little in normal cells, inhibitors of this enzyme has been expected to be new anticancer drugs. Here, we examined the inhibitory abilities to the human GLO I of anthocyanidins, such as delphinidin, cyanidin and pelargonidin. Among them, delphinidin was found to have the most potent inhibitory effect on human GLO I. Also, only delphinidin-induced apoptosis in HL-60 cells in a dose- and time-dependent manner. Furthermore, we determined a pharmacophore for delphinidin binding to the human GLO I by computational simulation analyses of the binding modes of delphinidin, cyanidin and pelargonidin to the enzyme hot spot. These results suggest that delphinidin could be a useful lead compound for the development of novel GLO I inhibitory anticancer drugs.


Assuntos
Antocianinas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Inibidores Enzimáticos/farmacologia , Frutas/química , Lactoilglutationa Liase/antagonistas & inibidores , Antocianinas/química , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Cristalografia por Raios X , Fragmentação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-Atividade , Fatores de Tempo , Células Tumorais Cultivadas
18.
Bioorg Med Chem ; 16(9): 4854-9, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18387304

RESUMO

Ac-DNLD-CHO is a novel caspase-3 specific peptide inhibitor that was rationally designed by our computational strategy. The specificity was shown to be due to the specific interaction of NLD moiety with the active site of caspase-3 on the basis of docking mode and site-directed mutagenesis analyses. Here, we computationally screened non-peptidic small molecular inhibitors of caspase-3 from our chemical library using a reliable pharmacophore derived from the specific binding mode of NLD. Through in vitro enzyme assay of the screened candidate compounds, we discovered a novel caspase-3 specific small molecular inhibitor, CS4566, which has a unique scaffold structure. The binding mode of CS4566 to caspase-3 mimics that of NLD, especially LD moiety. This represents a promising lead compound for creating non-peptidic pharmaceuticals for caspase-mediated diseases, such as neurodegenerative disorders.


Assuntos
Inibidores de Caspase , Simulação por Computador , Inibidores de Cisteína Proteinase/farmacologia , Naftóis/síntese química , Naftóis/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/química , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Naftóis/química , Bibliotecas de Moléculas Pequenas , Estereoisomerismo , Relação Estrutura-Atividade
19.
Inorg Chem ; 47(7): 2747-54, 2008 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-18321042

RESUMO

8-Benzenesulfonyloxy-5- N,N-dimethylaminosulfonylquinolin-2-ylmethyl-pendant cyclen (BS-caged-L(4), BS = benzenesulfonyl) was designed and synthesized as a "caged" derivative of a previously described Zn(2+) fluorophore, 8-hydroxy-5- N,N-dimethylaminosulfonylquinolin-2-ylmethyl-pendant cyclen (L(4)) (cyclen = 1,4,7,10-tetraazacyclododecane). In the absence of metal ions and in the dark, BS-caged-L(4) (10 microM) showed negligible fluorescence emission at pH 7.4 (10 mM HEPES with I = 0.1 (NaNO3)) and 25 degrees C (excitation at 328 nm). Addition of Zn(2+) induced an increase in the UV/vis absorption of BS-caged-L(4) (10 microM) at 258 nm and a significant increase in fluorescence emission at 512 nm. These responses are results from the formation of Zn(H-1L(4)) by the hydrolysis of the sulfonyl ester at the 8-position of the quinoline unit promoted by the Zn(2+)-bound HO(-). Improvement of cell membrane permeation in comparison with L(4) is also described.


Assuntos
Compostos Heterocíclicos com 1 Anel/síntese química , Hidrogênio/química , Zinco/química , Cádmio/química , Cátions Bivalentes/química , Corantes Fluorescentes/química , Compostos Heterocíclicos com 1 Anel/química , Concentração de Íons de Hidrogênio , Hidrólise , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Espectrofotometria , Compostos de Enxofre/química
20.
Bioorg Med Chem ; 16(7): 3969-75, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18258440

RESUMO

Glyoxalase I (GLO I) is the rate-limiting enzyme for detoxification of methylglyoxal (MG), a side product of glycolysis, which is able to induce apoptosis. Since GLO I is known to be highly expressed in the most tumor cells and little in normal cells, specific inhibitors of this enzyme have been expected as effective anticancer drugs. The purpose of this study is a good construction of the human GLO I/inhibitor pharmacophore to obtain unique human GLO I inhibitory seed compounds for the development of useful anticancer drugs. Here, we selected natural flavonoid compounds that possess a plane configuration of cis C-4 ketone and C-5 hydroxy groups as the substrate (MG) transition-state mimetic structure. These compounds were examined the inhibitory abilities to human GLO I activity and analyzed their structure-activity relationships to determine an important pharmacophore of flavonoids for the human GLO I binding. Our results point to the contribution of hydroxy groups at the B ring of flavonoids to the effective inhibition of the human GLO I. Based on the binding mode of flavonoids, we constructed the human GLO I/inhibitor pharmacophore. This work delivers the first three-dimensional (3D) structural data and explains certain flavonoids interact specifically with the human GLO I.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Lactoilglutationa Liase/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Hidroxilação , Cetonas/química , Estrutura Molecular , Spodoptera , Relação Estrutura-Atividade
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